Colon cancers are the second leading cause of cancer-related deaths in the United States. Although the genetic alternations associated with initiation and progression of colon cancers are well defined, the mechanisms by which tumors invade and metastasize require further investigation. Metastasis of colon cancers is the major cause of patient deaths. Thus, understanding the mechanisms of tumor metastasis is important and likely to be clinically useful. RON (Recepteur d'Origine Nantais) is a receptor tyrosine kinase belonging to the MET proto-oncogene family. Recent studies have shown that RON and its variants are highly expressed and constitutively activated in the majority of colon carcinoma cells, but not in normal colon mucosa or benign lesions. Moreover, RON activation induces a unique genetic program leading to cell dissociation, migration and matrix invasion. These data suggest that RON might be involved in the invasive growth and metastasis of colon cancers in vivo. The goal of this project is to study the cellular and molecular mechanisms by which RON mediates the invasive growth of colon carcinoma cells. The hypotheses underlying this proposal are: a) Cellular disorganization and genetic changes during the progression of colon cancers results in increased RON expression and its variant formation; b) RON has oncogenic/metastatic potential which is essential for the acquisition of motile-invasive phenotypes in colon cancers; and c) Acquisition of motile-invasive phenotypes by colon cancer cells is determined by the intracellular domains of RON that transduce a unique signaling pathway(s). To test these hypotheses, our studies will focus on: 1. Correlating RON and its variant expression in colon carcinoma cells with invasive behavior and clinical outcomes; 2. Determining the potential cellular mechanisms responsible for the abnormal RON expression and activation; 3. Studying how RON activation causes oncogenic and invasive activity in colon cancers cells; 4. Investigating the unique signaling pathway(s) of RON and its variants that elicit motile-invasive phenotypes in colon cancer cells. This work is important for several reasons. First, it will provide the basis for understanding the role of RON in the progression of colon cancers, particularly at the metastatic stages. Second, it will facilitate our understanding the mechanisms of how overexpression of a particular receptor tyrosine kinase results in the invasive growth and metastasis of colon cancers. Further, this work may lead to novel approaches for decreasing the metastasis of colon cancers in vivo.